Abstract

Background—The development of endocrine tumours of the duodenopancreatic area (ETDP) is thought to be slow, but their natural history
is not well known. The aim of this study was to determine the factors that influence survival of patients with ETDP.

Patients/Methods—Eighty two patients with ETDP (44 non-functioning tumours, 23 gastrinomas, seven calcitonin-secreting tumours, four glucagonomas,
three insulinomas, one somatostatinoma) followed from October 1991 to June 1997 were included in the study. The following
factors were investigated: primary tumour size, hormonal clinical syndrome, liver metastases, lymph node metastases, extranodular/extrahepatic
metastases, progression of liver metastases, local invasion, complete resection of the primary tumour, and degree of tumoral
differentiation. The prognostic significance of these factors was investigated by uni- and multi-variate analysis.

Conclusion—Liver metastases are a major prognostic factor in patients with ETDP. Progression of liver metastases is also an important
factor which must be taken into account when deciding on the therapeutic approach. The only other independent prognostic factors
are tumoral cell differentiation and complete resection of the primary tumour.

Endocrine tumours of the duodenopancreatic area (ETDP) are rare lesions with a supposedly slow evolution1 which can be detected by symptomatic hormone overproduction (functioning tumours); patients with non-functioning tumours
tend to present with liver metastases at diagnosis.2 In all cases, the main challenge is the control of the tumoral process.

The prognostic factors of ETDP have not yet been clearly defined. The rarity of these tumours and their usually slow progression
have made it difficult to define their natural history. In addition, many studies have included both ETDP and carcinoid tumours
whereas these two entities should be considered separately.3 Moreover, traditional histological and morphological assessments of the primary tumour (nuclear pleomorphism, prominent nucleoli,
and infiltration of peritumoral acinar tissue) are not effective for predicting malignant behaviour.4 Only the presence of distant metastases, mainly hepatic or nodal, is a definitive criterion of malignancy.

Some recent studies have tried to assess new criteria, especially the determination of cell proliferation,5-9 in the discrimination of benign and malignant ETDP. However, none of these markers is routinely used in the management of
patients with ETDP.

The present study evaluated the prognostic significance of several routinely used parameters in a large single centre series
of patients with ETDP.

Patients and Methods

patients

Eighty two consecutive patients with ETDP seen in the Gastroenterology Department of Beaujon University Hospital were included
in a retrospective study between October 1991 and June 1997.

Table 1 summarises the relevant clinical characteristics of the patients. There were 45 men and 37 women. Median age was 49.5 years
(range 22–79). Median duration of follow up was 32 months (range 1–204) from diagnosis and 50 months (range 2–514) from the
first clinical signs. Multiple tumours were observed in the duodenum in two patients with gastrinomas and in the pancreas
in one patient with an insulinoma. Extranodular/extrahepatic metastases (n = 15) were found in the bones (n = 8), the peritoneum
(n = 5), the lungs (n = 4), the brain (n = 2), the adrenal glands (n = 2), and the skin (n = 1).

For all other patients with ETDP (n = 59), the diagnosis was histologically confirmed by conventional and immunohistochemical
techniques (neuron specific enolase, chromogranin A, and staining with specific peptides according to tumoral secretion).
For patients who had not received surgery (n = 19), diagnosis was based on analysis of biopsy samples of the primary tumour
(n = 6), of liver metastases (n = 11), or of lymph node metastases (n = 2).

Serum hormone levels (gastrin, vasoactive intestinal polypeptide, insulin, glucagon, calcitonin, somatostatin) were determined
in all patients. The tumour was designated as non-functioning when no specific clinical signs were induced by hormonal overproduction.
Among the 44 patients with non-functioning tumours, increases in plasma levels of both somatostatin and calcitonin were observed
in four, and increases in plasma levels of several peptides (vasoactive intestinal polypeptide, gastrin, glucagon, somatostatin,
calcitonin) were observed in three.

methods

The prognostic significance of the following variables was analysed: liver metastases (LM), progression of LM, lymph node
metastases, extranodular/extrahepatic metastases, size of the primary tumour, clinical syndrome of hormonal hypersecretion,
local invasion by the primary tumour, complete resection of the primary tumour, and degree of tumoral cell differentiation.

The prognostic significance of the results of medical treatment was not considered, since procedures, drugs, and routes of
administration varied and it was not possible to define a homogeneous subgroup of patients.

Localisation of the primary tumour and of distant metastases was achieved in all patients by abdominal ultrasonography and/or
computed tomography (CT) scan, and chest x ray. Endoscopic ultrasonography of the duodenopancreas was performed in 56 patients, and somatostatin receptor scintigraphy
was performed in 47. Other radiological techniques (cerebral CT scan, bone scintigraphy) were performed according to clinical
signs.

The size of the primary tumour at diagnosis, expressed as the largest measurable diameter of the tumour, was assessed by laparotomy
(n = 57) or radiological techniques (ultrasonography and/or CT scan and/or endoscopic ultrasonography; n = 26). The survival
rate of patients with a primary tumour of less than 3 cm was compared with those with a primary tumour of 3 cm or above in
diameter.1112

The size of LM was calculated at diagnosis as the sum of the products of the two largest perpendicular diameters of measurable
lesions. Tumoral progression of LM was defined before treatment by an increase in the size of LM by at least 25% or the appearance
of new liver lesions when comparing CT scans performed at an interval of at least three months. Thus, when surgery or chemotherapy
was performed within three months of diagnosis of LM, tumoral progression of LM could not be evaluated.

Local invasion of neighbouring organs was identified at laparotomy with histological confirmation (n = 16), or was identified
by CT scan (n = 10).

Fifty seven patients had abdominal exploratory surgery. Complete resection of the primary tumour (n = 42) was defined surgically
as a macroscopically complete resection and histologically by tumour-free resection margins. Complete resection was performed
in 13 patients without metastases, in 10 patients with only lymph node metastases (all resected), and in 19 patients with
LM in whom 12 were synchronous (two non-resected, five completely resected, and five partially resected) and seven were metachronous
(one had partial resection of LM).

histology

The degree of tumoral differentiation was reviewed by a single pathologist, in tissue obtained by either surgical resection
(n = 52) or fine-needle biopsy (n = 21) guided by ultrasonography or CT scan. The tumours were classified into three groups
based on the classification for pulmonary endocrine tumours.13 The first group included insular or acinar patterns. Nuclei were small and no necrosis was seen. The second group was characterised
by a lesser degree of architectural organisation with cellular crowding and pleiomorphism. The third group included small
and large cell carcinomas. Patients with well differentiated tumours (first two groups) were compared with those with poorly
differentiated tumours. In three cases, the tissue samples were insufficient to draw firm conclusions, and six tumours could
not be histologically confirmed (gastrinomas).

statistical analysis

The primary outcome index was overall survival from the date of diagnosis to the last date of follow up or death. Univariate
analysis was performed to compare the death rates in the different subgroups of patients by the χ2 test or Fisher’s exact test. Actuarial survival probabilities were calculated by the Kaplan-Meier method, and compared by
the log rank test. Multivariate analysis was performed with the Cox proportional hazards model. The variable “liver metastases”
was forced in the model because there were no deaths in the group without LM. p<0.05 was considered to be statistically significant.

Results

Twenty eight patients (34%) died 17 (1–110) months (median (range)) after diagnosis. In 27 cases, deaths were related to the
tumoral progression of LM. One patient died from postoperative septicaemia after surgery for a gastrinoma with multiple LM.

Univariate analysis of prognostic factors in 82 patients with endocrine tumours of duodenopancreas

The median survival time of patients with or without surgical resection of the primary tumour was 110 and 34 months respectively
(RR of death 4.85; 95% CI 1.96 to 12.05; p = 0.0002). In patients with poorly or well differentiated tumours, median survival
time was 5 and 110 months respectively (RR 11.75; 95% CI 4.38 to 31.53; p = 0.0001). In patients with or without extranodular/extrahepatic
metastases, survival time was 11 and 110 months respectively (RR 4.4; 95% CI 2 to 9.5; p = 0.0001). For the other variables,
the death rate in one group was not high enough to calculate a median difference in survival.

To assess factors associated with LM, we compared the frequency of patients with LM in several groups. We found a significant
increase in LM among patients with a primary tumour ⩾3 cm (p = 0.001), with non-functioning tumours (p = 0.043), with lymph
node metastases (p = 0.001), with extranodular/extrahepatic metastases (p = 0.003), and with locoregional tumoral involvement
(p = 0.001) (table 3).

Frequency of liver metastases in 82 patients with endocrine tumours of the duodenopancreatic area, according to selected variables

Comparisons of actuarial survival curves in patients with and without LM, with completely and incompletely resected primary
tumours, and with good and poor tumour cell differentiation are shown in figs 1, 2, and 3respectively.

Overall survival after diagnosis among 82 patients with endocrine tumours of the duodenopancreatic area, according to the
presence of liver metastases (log rank test; p = 0.0001). The asterisks indicate the number of patients at risk.

Overall survival after diagnosis among 82 patients with endocrine tumours of the duodenopancreatic area, according to complete
resection of the primary tumour (log rank test; p = 0.0001). The asterisks indicate the number of patients at risk.

Overall survival after diagnosis among 73 patients with endocrine tumours of the duodenopancreatic area according to the cell
differentiation of the primary tumour (log rank test; p = 0.0001). The asterisks indicate the number of patients at risk.

multivariate analysis

The presence of LM was the most significant prognostic factor. The relative risk of death associated with LM was 8.3 (95%
CI 3.6 to 19.4; p<0.00001). When the presence of LM is taken into account, tumour cell differentiation (conditional RR of
death associated with poor differentiation 8.11; 95% CI 3.05 to 21.60; p = 0.0001) and resection of the primary tumour (RR
of death associated with no complete resection 4.85; 95% CI 1.94 to 12.05; p = 0.0007) remain significant independent indicators
of prognosis (table 4).

Discussion

During the study period (October 1991 to June 1997) in this series of 82 patients with ETDP, 28 patients died after a median
follow up of 17 months (range 1–110). In 27 cases, death occurred as a result of tumoral progression in patients with LM.
The rate of malignancy (defined by the presence of metastatic spread to lymph nodes, liver or elsewhere) was 77%. These figures
support those in the literature and vary depending on hormonal secretion: 5 to 10% for insulinomas,14 70 to 75% for glucagonomas,1523 to 90% for gastrinomas,1617 and 60 to 92% for non-functioning tumours.218

In our series, the presence of LM was the most significant survival factor identified by uni- and multi-variate analysis,
with a RR of death of 8.3 (95% CI 3.5 to 19.4; p = 0.0001). The five year survival rates in patients with and without LM were
40 and 100% respectively, and the median survival was 47 months. These figures are close to those reported in the literature.
Studies performed in patients with Zollinger-Ellison syndrome reported a five year survival rate of 20–50% in patients with
LM compared with 65–100% in those without.161719 In one series of 35 patients with digestive endocrine tumours (20 gastrinomas, 12 carcinoid tumours, and three other digestive
endocrine tumours) and LM, the five year survival rate was 70%.20

The progressive (>25% increase on two consecutive CT scans) or non-progressive pattern of LM was very significantly associated
with survival, and helped to identify two subgroups of patients with an actuarial five year survival rate of 34 and 100% respectively.
Mignonet al20 reached similar conclusions in 35 patients with LM of digestive endocrine tumours. These results favour the current therapeutic
approach of reserving chemotherapy for LM for those patients with progressive or symptomatic LM. It also justifies radiological follow up of patients with LM, particularly as predictive factors of evolution have not been
established.

The degree of tumoral differentiation was an independent prognostic factor from the presence of LM. Poorly differentiated
tumours form a subgroup of anaplastic neuroendocrine carcinomas with marked cellular atypia,21 which are characterised by rapid tumoral progression and were associated with a median survival of five months in the present
study.

Complete resection of the primary tumour was the only other prognostic factor independent of the presence of LM. The RR of
death in the absence of resection of the primary tumour was 4.85 (95% CI 1.94 to 12.05). In the literature, the role of extensive
surgical resection is controversial. McEntee et al22showed that resection of the primary tumour and hepatic cytoreduction was possible with acceptable mortality and morbidity
in 37 patients with endocrine pancreatic or carcinoid tumours and LM. The only benefit identified occurred in limited and
completely resectable metastatic lesions leading to complete or incomplete remission of symptoms in 85 and 15% of the patients
respectively, with a median duration of 26 months. No benefit in survival was shown. In contrast, incomplete resections were
associated with a relapse within 12 months in all cases. Carty et al23 compared 17 patients with pancreatic endocrine tumours who had received extensive resection of all tumoral lesions with 25
inoperable patients: the five year survival rates were 79 and 28% respectively. This study also noted that the survival rate
in operated patients did not improve when metastastic lesions were very advanced. In another study,20 there was no improvement in survival in 35 patients with LM of digestive endocrine tumours after resection of the primary
tumour. Combined resection of the primary tumour and LM seems to be beneficial in a selected population without extensive secondary
lesions.

Interestingly, the presence of extrahepatic metastases was no longer a prognostic factor of survival once correction for the
presence of LM had been made. These results confirm those of Stabileet al16 and Weberet al11 who showed that the survival of 65 and 185 patients with gastrinomas respectively was not influenced by the presence of nodal
metastases.

When the size of the primary tumour at diagnosis was 3 cm or more, the five year survival rate was 47% compared with 88% below
this threshold (p = 0.003). This parameter did not remain significant on multivariate analysis, probably because LM were associated
with larger primary tumours: 77% of patients with a primary tumour ⩾3 cm had LM compared with 35% of those with a primary
tumour < 3 cm. Weberet al11 previously showed in 185 patients with gastrinomas that the rate of LM was significantly greater when the primary tumour
was ⩾3 cm. Klöppelet al12 considered that a size greater than 3 cm (and/or the presence of vascular invasion at histological examination) was predictive
of aggressive development in non-functioning endocrine tumours. This threshold was lowered to 2 cm for functioning digestive
endocrine tumours.

The traditionally poor prognosis of non-functioning tumours is usually attributed to late diagnosis, and LM were already present
at diagnosis in 71% of our patients, compared with 47% in functioning tumours. In the literature, the rate of LM among patients
with non-functioning tumours is estimated to be between 60 and 92% of cases.218 Eriksson et al18 reported a five year survival rate of 42% in patients with non-functioning tumours compared with 80% in those with functioning
tumours. It has been suggested that more non-functioning tumours are anaplastic.21

conclusion

In this large single centre series of 82 patients with ETDP, the presence of LM was the factor that most strongly correlated
with survival, with an RR of death of 8.3. However, the progression of LM is an important prognostic factor which should be
taken into account when planning treatment in these patients. The degree of cellular differentiation had independent prognostic
value, and identified a small subgroup of anaplastic tumours with an extremely poor prognosis (median survival five months).
The only other independent factor predictive of survival was complete resection of the primary tumour. These results support
the strategy of combined surgical resection of the primary tumour and LM whenever possible.

(1995) Histopathology and immunopathology of the pancreatic endocrine tumors. in Endocrine tumors of the pancreas. Recent advances in research and management. eds MignonM, JensenRT (Karger, Basel), pp 99–120.